A hallmark of our PPG is the development of quantitative techniques to gain insight into physiological processes limiting the effective use of therapeutic agents. The primary scientific focus of this core involves three fields related by their bioengineering emphasis: intravital microscopy, mathematical modeling, and image analysis. Two other important functions of this core are:maintenance of computer systems and biostatistical guidance in experimental design and data interpretation. Each project relies on microscopy to quantify physiological and biophysical parameters. The core will therefore continue to pioneer new quantitative methods (e.g. in vivo multiphoton fluorescence correlation spectroscopy), continuing a long- standing tradition recently confirmed by three papers published in the New Technology section of Nature Medicine (2001,2003, 2004, 2005). The bioengineering core will also acquire and maintain optical equipment, and related electronic and photographic equipment for recording and analyzing images. Core leaders will instruct and assist researchers in the use of microscopy techniques and related image analysis software. Mathematical modeling will be used to help understand transport barriers on several length scales and for a variety of therapeutic agents. Whole body, organ, microscopic, and in vitro models have been developed and used successfully by the lab. In the proposed PPG this aspect of the bioengineering core will be essential in interpreting data in all projects, e.g. for analyzing vascular permeability data, interstitial flow and transvascular transport studies. Image analysis requires the collection, analysis, and visualization ofcomplex data obtained in all projects. As this involves considerable knowledge of software and hardware systems, this important need is best served with a core facility. Likewise, the maintenance of computer hardware, software, and networks is best performed with a knowledgeable computer systems manager. Finally, the quantitative aspects of our research methods require close collaboration with a biostatistician in all phases of the research: experimental design (protocols and animal calculations), analysis of experimental data, and careful estimation of model parameters with nonlinear regression techniques. The three research projects in this PPG could not be carried out if the services of the bioengineering core component were not available.